10-87933183-C-T

Position:

• chr10-87933183-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP2 PP3 PM2_Supporting BS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.424C>T (p.Arg142Trp) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score of this variant = 0.45) per Mighell et al. 2018 (PMID:29706350). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.PP3: REVEL score > 0.7 (score of this variant = 0.716).PM2_P: Absent in gnomAD. Although this variant has been observed de novo in published literature (PMID 38335860) and internal laboratory cases, many of these patients and several others did not have features consistent with PTEN Hamartoma Tumor syndrome (PMID 26534844). This variant occurs as a CpG dinucleotide site; such sites have an increased rate of spontaneous deamination leading to de novo mutation (PMID 16570853). We believe that de novo observations of this variant are most likely incidental findings due to the hypermutable nature of this nucleotide position, and are not awarding de novo criteria as evidence towards pathogenicity given the inconsistent phenotypes present. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000455/MONDO:0017623/003

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:7
• Conservation: PhyloP100: 4.54

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.424C>T	p.Arg142Trp	missense_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.943C>T	p.Arg315Trp	missense_variant	6/10
PTEN	NM_001304718.2	c.-327C>T		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.424C>T	p.Arg142Trp	missense_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251366 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:7

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:2

Uncertain significance, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	May 17, 2024	NM_000314.8(PTEN):c.424C>T (p.Arg142Trp) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). BS3_P: Well-established functional studies show no deleterious effect: Phosphatase activity >0 (score of this variant = 0.45) per Mighell et al. 2018 (PMID: 29706350). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score of this variant = 0.716). PM2_P: Absent in gnomAD. Although this variant has been observed de novo in published literature (PMID 38335860) and internal laboratory cases, many of these patients and several others did not have features consistent with PTEN Hamartoma Tumor syndrome (PMID 26534844). This variant occurs as a CpG dinucleotide site; such sites have an increased rate of spontaneous deamination leading to de novo mutation (PMID 16570853). We believe that de novo observations of this variant are most likely incidental findings due to the hypermutable nature of this nucleotide position, and are not awarding de novo criteria as evidence towards pathogenicity given the inconsistent phenotypes present. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 142 of the PTEN protein (p.Arg142Trp). This variant is present in population databases (rs746152219, gnomAD 0.0009%). This missense change has been observed in individual(s) with Cowden syndrome, breast and/or ovarian cancer and endometrial cancer (PMID: 16506206, 25669429, 26534844). ClinVar contains an entry for this variant (Variation ID: 197662). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTEN protein function. Experimental studies have shown that this missense change affects PTEN function (PMID: 29785012). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2023	Observed in at least one individual reported to meet Cowden syndrome or relaxed Cowden syndrome-like criteria (Nizialek et al., 2015); Reported as a variant of uncertain significance in at least one individual with familial breast cancer whose history was not suggestive of Cowden syndrome (Li et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28984400, 15492994, 17924977, 21470976, 16506206, 15923161, 29706350, 29785012, 23116406, 32384322, 33879063, 35338148, 28178681, 25669429, 26534844, 24475377) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2014	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	This missense variant replaces arginine with tryptophan at codon 142 of the PTEN protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Cowden and Cowden-like syndrome and multiple unaffected family members (PMID: 25669429), in an individual with a personal or family history of breast/ovarian cancer (PMID: 26534844), and in two individuals with endometrial cancer (PMID: 16506206). This variant has been identified in 1/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 07, 2022	The p.R142W variant (also known as c.424C>T), located in coding exon 5 of the PTEN gene, results from a C to T substitution at nucleotide position 424. The arginine at codon 142 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). This variant has also been detected in a single family with a history of breast and/or ovarian cancer (Li J et al. J. Med. Genet., 2016 Jan;53:34-42). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 27, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29785012]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [Myriad internal data]. -

Autistic behavior;C2243051:Macrocephaly;C4022738:Neurodevelopmental delay Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jun 21, 2021

ACMG classification criteria: PM2 moderate, PP2 supporting, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.72
Sift	Benign	0.033	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.47		Gain of ubiquitination at K147 (P = 0.0645);
MVP		0.95
MPC		2.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746152219; hg19: chr10-89692940; COSMIC: COSV64296832;